Liver disease is a cause of substantial morbidity and mortality in the U.S., and cholestasis (impairment of bile flow) is a common and devastating manifestation of liver disease. The experiments in this revised application are focused on increasing our understanding of the genetic etiology underlying development of cholestatic liver disease;such a goal is amongst those articulated in the "Action Plan for Liver Disease Research," a report prepared by the NIH in 2004. The genetic studies in this proposal include investigation of a rare, Mendelian disease, as well as a more common cholestatic disorder of presumed complex etiology. In Specific Aim 1, the genetic lesion(s) responsible for lymphedema-cholestasis syndrome (LCS), located in the LCS1 candidate region on chromosome 15, will be determined. Results of this Aim will increase understanding of the etiology of cholestasis, and provide insight into the biological interplay between the liver and the lymphatic system. In Specific Aims 2-4, recent progress in understanding the genetic underpinnings of rare cholestatic disorders will be leveraged to increase our knowledge regarding a more common disorder intrahepatic cholestasis of pregnancy (ICP). ICP endangers babies, increasing the risk of premature delivery, fetal distress, and intrauterine death. In Specific Aim 2, a study cohort of 400 women diagnosed with intrahepatic cholestasis of pregnancy (ICP), and matched controls, will be established;half of this cohort will be collected from the San Francisco Bay Area, and the other half, from Chile, where the disorder is particularly common. In Specific Aim 3, genes previously implicated in the genetic etiology of primary cholestatic disorders will be sequenced in DNA from these patients and controls to identify rare genetic variants that likely increase susceptibility to ICP. In Specific Aim 4, genotyping of single nucleotide polymorphisms (SNPs) in these genes will be performed in the Latina portion of the sample, with correction for admixture, to test the hypothesis of association between SNPs in these genes and susceptibility to ICP. The results of the studies in Specific Aims 2-4 will increase our understanding of the genetic etiology of this clinically important cause of perinatal mortality and morbidity. As a result of the program of research described in this proposal, our knowledge of the etiology of cholestasis will be significantly advanced.